The technological revolution in genetics is beginning to yield results for ADHD. Rare copy number variants have been identified that confer risk to ADHD providing the first molecular evidence for risk to the disease. In contrast, genome-wide association studies of single nucleotide polymorphisms (SNPs), to date, have yet to unequivocally identify risk factors that predisposes to ADHD with the most recent meta-analysis totaling 2,064 trios, 896 cases and 2,455 controls. This lack of progress stands in stark contrast to the strong evidence for heritability of ADHD, attention and activity levels from twin and family studies. Among the several possible explanations for this disconnect is that rare SNPs confer risk to ADHD. Given that rare CNVs clearly play a role in the pathophysiology of ADHD, it is not unreasonable to expect that rare SNPs of large effect may also exist. We are proposing the first study to comprehensively define the role of rare SNPs drawn from the coding region of genes in the etiology of the disorder. We will do so by using the newly developed exome chip, an innovative, cost-effective technology that will allow us to assay approximately 200,000 rare SNPs found in the coding region of the human genome. This exome chip assay should capture nearly all SNPs at an allele frequency threshold of 0.1% in European populations and captures an estimated 80% of the variants with an allele frequency of 0.02%. Our specific aims are: Aim 1: Assay Rare Variation in 1,800 ADHD Trios. We will generate exome chip data on a total of 1,800 ADHD trio families to identify rare functional inherited variation that predisposes to ADHD. We will assay approximately 200,000 rare SNP mutations in the exome. Aim 2: Comprehensively Analyze the Identified Rare Variation. Upon completion of the genotyping assays, we will perform single-locus and regional association analysis of the exome chip data. We will then extend these primary analyses by interrogating genes and pathways by leveraging bioinformatics tools to improve the power to detect genes and to more clearly interpret our primary results. Aim 3: Share All Data with the Scientific Community. We are committed to ensuring that all data generated by this application will be deposited in dbGaP and any other database required by NIH regulations. Upon completing this project, we expect to provide the field with a treasure trove of rare DNA variants that can be followed up with functional, biologica assays. This work is significant because ADHD is a common disorder of childhood associated with school failure, psychiatric comorbidity and psychosocial disability in childhood. Most cases persist into adulthood when the disorder is additionally associated with occupational failure, criminality, traffic accidents, substance abuse and increased medical health care utilization. Health economic studies suggest that, in adulthood, the cost of ADHD to society is between $77.5 and $115.9 billion each year. Current treatments are only partially effective, and no preventive treatments exist. New treatment targets are needed to develop better medications for treating ill patients and, perhaps, for preventing the disorder in susceptible people. PUBLIC HEALTH RELEVANCE: We will generate exome chip data on 1,800 ADHD probands and their parents. The exome chip provides the first look at rare variation in the coding regions of genes that is heavily enriched for potential biological function. We will comprehensively analyze this data at a single locus, gene, and biological pathway level. This experiment promises to quantify the impact of rare mutations on ADHD.